Methods for treating headaches

ABSTRACT

Apparatus, methods, and kits for treating symptoms associated with common ailments, such as headaches, rhinitis, asthma, epilepsy, nervous disorders and the like, are provided. The apparatus comprises dispensers for carbon dioxide and other therapeutic gases. The methods comprise delivering small volumes of these gases to patients in a manner where the gas infuses into a body region in order to bathe the mucous membranes therein. It has been found that even very short exposure of patients to small volumes and high concentrations of such gases can provide significant relief from symptoms.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/200,649 (now U.S. Pat. No. 7,748,379), filed Aug. 9, 2005; which is adivisional of U.S. application Ser. No. 09/614,389 (now U.S. Pat. No.7,017,573), filed Jul. 12, 2000; which claims the benefit of U.S.Provisional Application Nos. 60/143,164, filed on Jul. 12, 1999;60/148,736, filed on Aug. 16, 1999; 60/164,125, filed on Nov. 8, 1999;and 60/185,495 filed on Feb. 28, 2000, under 37 CFR §1.78. The fulldisclosures of each of these applications are incorporated herein byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to medical apparatus andmethods. In particular, the present invention relates to methods anddevices for delivering carbon dioxide and other gases to patients forrelieving symptoms associated with headache (e.g., migraine headaches,tension-type headaches, cluster headaches), jaw pain, facial pain (e.g.,trigeminal neuralgia), allergies (rhinitis and conjunctivitis), asthma,nervous disorders (e.g., epilepsy, Parkinson's), and other commonailments.

A walk through the headache and allergy section of any pharmacy quicklyreveals that there is wide spread interest in remedies for relievingsymptoms commonly associated with headaches, allergies, asthma, andother common ailments. The commonly available therapies include oralmedicines, nasal sprays, oral inhalers, nasal inhalers, eye drops, andnose drops, and probably other devices and approaches that have beendeveloped over the years. Still more possible therapies are availablefrom the pharmacy with a prescription from a patient's doctor (e.g.,injectables, inhalables). Despite the very large number of therapieswhich are available, no one therapy meets all patient needs, and many ofthe therapies suffer from very significant shortcomings. For example,present day therapies are slow-acting, have numerous adverse sideeffects (e.g., nausea, drowsiness, rebound headache from analgesicoveruse, rebound congestion from decongestant overuse, dizziness,sedation, addiction, and numerous others), have low efficacy, and arecontraindicated for a large portion of patients (e.g., those withhypertension, coronary artery disease, cerebrovascular disease, pepticulcers, pregnancy, concurrent medications that would interact, children,elderly, and others). Suffice it to say that there is a continuinginterest in providing improved methods and apparatus for treating suchcommon symptoms and ailments.

The use of diluted carbon dioxide by inhalation for treating symptomsrelated to headaches, allergies, asthma, nervous disorders, and othercommon ailments was demonstrated in the 1940's and 1950's. The treatmentprotocols generally rely on breathing masks or other equipment fordelivering relatively large volumes of dilute carbon dioxide for thepatient to inhale through the mouth and/or the nose into the lungs untilthey become unconscious. The efficacy of this treatment depends upon thesystemic effects of the inhaled gas and therefore require large volumesof gas. Typical carbon dioxide volumes inhaled were in the range from0.5 to 25 liters of 30% to 70% carbon dioxide diluted in oxygen during asingle treatment which was repeated several times a week for 25 to 50treatments. While the use of inhaled carbon dioxide has proven to bequite effective for a number of indications, the wide spread use ofcarbon dioxide delivered in this manner never became popular. It islimited by the necessity of making the patient unconscious, the lengthof the treatment time and course, and the necessarily large, bulkynon-portable gas cylinders and physician administration it requires.Most prior systems are so large and heavy they must be wheeled aboutusing a dolly or a cart, and thus do not lend themselves to use outsideof the hospital or home. While hand-held carbon dioxide dispensers havebeen proposed (for other purposes such as the treatment ofhyperventilation), they are designed to deliver large volumes of dilutecarbon dioxide for inhalation.

For these reasons, it would be desirable to provide improved apparatusand methods for treating the symptoms normally associated withheadaches, allergies, asthma, and the like. Such apparatus and methodsshould provide small volumes of gas for convenient use away from thehome, substantially immediate relief of symptoms, safety with few or noside effects, efficacy without requiring unconsciousness, efficacy in alarge number of patients, therapy for those contraindicated for presentday therapies, therapy without interaction with concurrent medications,low cost, a long life (in at least some embodiments), and permit thepatient to administer the therapy and adapt the product usage formaximum comfort and effectiveness. At least some of these objectiveswill be met by the inventions described hereinafter.

2. Description of the Background Art

U.S. Pat. No. 3,776,227, describes a hand-held dispenser that deliversdilute carbon dioxide intended for the treatment of hyperventilation byinhalation. In addition, this hand-held dispenser is not designed todeliver carbon dioxide at high concentrations which are unbreathable.Other inhalation devices, systems, and methods for delivering carbondioxide and other gases and aerosols to patients are described in U.S.Pat. Nos. 3,513,843; 3,870,072; 3,974,830; 4,137,914; 4,554,916;5,262,180; 5,485,827; and 5,570,683.

Gas therapy for the treatment of headaches, allergies, asthma, and otherconditions as well as associated physiology is described in thefollowing references in the medical literature:

A. Carbon Dioxide Therapy

-   Diamond, S. Migraine headache—its diagnosis and treatment. 13^(th)    Annual Practicing Physician's Approach to the Difficult Headache    Patient, Rancho Mirage, Calif., Feb. 5-19, 2000-   Fisher H K et al., Am Rev Respir Dis 114(5):861, November 1976-   Fisher H K et al., Am Rev Respir Dis 101:855-896, 1970-   Gillman M A et al, Br J Psychiatry 159:672-5, 1991-   Grosshans V A et al., Z Gesamte Inn Med 42(23):667-70, 1987-   Harrowes W M C, Selinger Z Fractional administration of carbon    dioxide in the treatment of neuroses, in Carbon Dioxide Therapy A    Neurophysiological Treatment of Nervous Disorders. Second Edition.    LJ Meduna Ed, Charles C. Thomas publisher, Springfield, Ill. 1958-   Jozefowicz R F Neurologic Manifestations of Systemic Disease    7(3):605-616, August 1989-   LaVerne A A Dis Nerv System 14:5, 1953-   Leake C D et al, Calif West Med 31:20, 1929-   Loevenhart A S et al. JAMA 92(11), 1929-   MacRae, D. Carbon dioxide in pediatrics, in Carbon Dioxide Therapy A    Neurophysiological Treatment of Nervous Disorders. Second Edition.    LJ Meduna ed, Charles C. Thomas publisher, Springfield, Ill., 1958-   Marcussen R M, Wolff H G, Arch Neurol Psychiatry 63:42-51, 1950-   Meduna L J Dis Nerv System 8(2), 1947-   Meduna L J J Nerv & Ment Dis 108:373, 1948-   Meduna L J Ed, Carbon Dioxide Therapy A Neurophysiological Treatment    of Nervous Disorders. Second Edition. Charles C. Thomas publisher,    Springfield, Ill. 1958-   Moriarty J D Prognosis with carbon dioxide therapy, including the    epinephrine-mecholyl test (Funkenstein test), in Carbon Dioxide    Therapy A Neurophysiological Treatment of Nervous Disorders. Second    Edition. LJ Meduna Ed, Charles C. Thomas publisher, Springfield,    Ill., 1958-   Moriarty J D J Clin & Exper Psychopath 13(3), 1952-   National Headache Foundation. A patients guide to migraine    prevention & treatment, Chicago, Ill., August 1996.-   Rodarte J R et al., Resp Physiol 17:135-145, 1973-   Singh V et al., Lancet 335:1381-3, 1990-   Wilkinson W E Some clinical observations pertaining to the effects    of carbon dioxide on the biology of mental disease, in Carbon    Dioxide Therapy A Neurophysiological Treatment of Nervous Disorders.    Second Edition. LJ Meduna Ed, Charles C. Thomas publisher,    Springfield, Ill., 1958-   Wilmoth D F et al., AACN Clin Issues 7(4):473-81, November 1996

B. Nitric Oxide Therapy

-   Pagano D et al., Eur J Cardiothorac Surg 10(12): 1120-6, 1996-   Ream R S et al., Crit Care Med 27(5):989-96, May 1999-   Schenk P et al., Ann Emerg Med 33(6):710-4, June 1999

C. Helium Therapy

-   Hollman G et al Crit Care Med 26(10):1731-6, October 1998-   Jolliet P et al Crit Care Med 27(11):2422-9, November 1999-   Schaeffer E M et al Crit Care Med 27(12):2666-70, December 1999

D. Physiology

-   Aizawa et al., Eur Respir J 13(4):775-80, April 1999-   Cha E J et al., J Appl Physiol 62(4):1544-50, April 1987-   Fiermonte G et al. Acta Neurol Scand 92(2):166-9, August 1995-   Glovsky M M Cur Opin in Pulm Med 4:54-58, 1998-   Leake C D Sci Monthly 20:320, 1925-   Loh E et al., Ann Thorac Surg 67(5):1380-5, May 1999-   Lorente de No'R Studies of the Rockefeller Institute 131:148-194,    1947-   Nielsen T M et al., Acta Physiol Scand 98(2):192-9, October 1976-   Saqueton C B et al., Am J Physiol 276(6 Pt 1):L925-L932, June 1999-   Schuttauf F et al Opthalmologe 95(4):225-8, April 1998-   Sterling G M et al., J of Appl Physiol 32(1):39-43, January 1972-   Tang A et al., Clinical Research 20:243, 1972

SUMMARY OF THE INVENTION

According to the present invention, methods, apparatus, and kits areprovided for relieving symptoms associated with a variety of commonailments, particularly headaches, rhinitis, asthma, and epilepsy.Specific symptoms include head pain, jaw pain, facial pain, sinuscongestion, sneezing, itchy throat, itchy eyes, rhinorrhea, difficultybreathing, seizures, and the like. This list of ailments and symptoms isnot meant to be exhaustive, and the present invention may find use withother disorders where infusion with the treatment gases describedhereinafter are found to provide for symptomatic relief. The inventionsallow delivery of a small volume of therapeutic gas at highconcentration directly into the nasal passages locally withoutinhalation providing faster relief without the adverse side effects ofsystemic drugs that are ingested, injected, or inhaled.

The present invention relies on infusing or bathing the mucous membranesof a body region of a patient, e.g., nasal and/or oral and/or ocular,with a treatment gas that induces a therapeutic effect relievingsymptoms. An exemplary treatment gas is carbon dioxide but other gasessuch as nitric oxide, oxygen, isocapnic mixtures of gaseous acids,helium, and the like, will also find use. The therapeutic gases(referred to herein as “therapeutic gases”) may be used in asubstantially pure form without other gases, active agents, or othersubstances that dilute the therapeutic gas or that have other biologicalactivities. In other instances, however, the therapeutic gases may becombined with other gases, such as inert carrier gases, active gases,solids to form aerosols, liquid droplets to form aerosols, sprays,powders, or the like to potentiate (enhance) their effects. Conversely,these agents combined with the therapeutic gas can potentiate theeffects of the therapeutic gas. In such instances, the therapeutic gasesand mixtures may have biological activities in addition to the relief ofsymptoms accompanying common ailments, as described above. In allinstances, however, the carbon dioxide or other principle therapeuticgas will be delivered in a quantity and over a time course that resultsin the reduction or elimination of the symptom that is being treated. Apreferred aspect of the present invention is providing the patient withthe ability to select a rate of infusive gas flow and total gas dosethat are effective and tolerable for the particular patient, which flowrate and dose are generally much smaller than those employed in previousart.

The present invention provides for the desired symptomatic relief byinfusing the treatment gas into a nasal and/or oral cavity without thepatient necessarily inhaling the therapeutic gas. In particular, it hasbeen found that by having the patient not inhale the therapeutic gas,i.e., substantially prevent passage of the therapeutic gas into thetrachea or lungs by holding his or her breath or by breathing eithernasally or orally via the route not being infused with the therapeuticgas, the volume of the body region being treated is significantlyreduced. A relatively low volume of the carbon dioxide or othertreatment gas can thereby be used to achieve the desired therapeuticeffect. In addition, substantial exclusion from the lungs permits theuse of the treatment gas at high (chronically unbreathable)concentrations, often being substantially pure approaching 100%, whichis necessary to achieve maximum effective treatment via the nasal andoral mucosa. Furthermore, nasal or oral infusion of a chronicallyunbreathable mixture of an inert carrier gas with nitric oxide permitsdirect delivery of nitric oxide to the treated mucosa without theoxidation of nitric oxide that would occur if the carrier gas were achronically breathable mixture of nitric oxide with air or oxygen.

In the case of mild headaches, rhinitis, or similar conditions, a totalcarbon dioxide volume as low as one cubic centimeter (cc) delivered overa time as short as one second may achieve adequate symptomatic relief.Of course, for more severe symptoms, such as those associated withmigraine headache, the total treatment volumes of carbon dioxide andtreatment times may be much greater.

Nasal and/or oral administration of concentrated carbon dioxide withoutinhalation may provide adequate symptom relief for asthma due to thephysiologic phenomenon known as the nasobronchial reflex. In all cases,however, it is believed that the ability to successfully relieve thepatient's symptoms depends primarily on the total volume of treatmentgas delivered to the patient over a sufficiently long duration. That is,the rate at which the treatment gas is delivered has little effect, andgenerally the patient can use as rapid a delivery rate as the patientfinds comfortable or tolerable in order to achieve a target total dosageand reduce the amount of time needed for treatment. Guidelines fordosages and treatment times for infusion into a nasal and/or oral cavityfor common symptoms associated with particular ailments are set forth inthe Dosage Guideline below.

TABLE I DOSAGE GUIDELINE Treatment Total Time Dosage Flow Rate TypicalTypical (Range) Condition (cc/sec) (Range) (sec) (cc) Allergic Rhinitis:Mild 1-10  3 (1-5)  10 (2-20) Moderate 1-10 15 (2-30)  30 (2-60) Severe1-10 50 (3-79) 160 (12-350) Tension-Type Headache: Mild 1-10  5 (1-16) 30 (1-80) Moderate 1-10 10 (2-16)  50 (2-80) Severe 1-10 60 (24-135)300 (168-675) Migraine Headache: Mild 1-10 30 (15-50)  80 (40-150)Moderate 1-10 60 (23-115) 160 (65-345) Severe 1-10 85 (30-180) 250(90-540)

The present invention also provides for the desired symptomatic reliefof allergic eye irritation (e.g., conjunctivitis) by infusing thetreatment gas over the eye, either behind a cupped hand over the eye orby other cup means that confine the therapeutic gas at highconcentration over the eye for the treatment period. The treatment timeand dose for treatment of the eye are similar to those for nasal andoral treatment.

A first aspect of the present invention provides methods for deliveringa therapeutic gas, e.g., carbon dioxide, nitric oxide, oxygen, isocapnicmixtures of gaseous acids, helium, and the like to a human patient. Themethod comprises generating a flow of the carbon dioxide or othertherapeutic gas, and infusing a mucous membrane or an eye with the flowof the gas. As described above, in order to limit and concentrate theinfusion of the therapeutic gas for nasal and/or oral treatment, thepatient usually refrains from inhaling the therapeutic gas while thenasal or oral mucous membrane is being infused or the patient breatheseither nasally or orally via the route not being infused with thetherapeutic gas. In this way, the volume of the nasal and/or oral cavitythat is filled by the flowing therapeutic gas is minimized and theconcentration of the gas maximized since the therapeutic gas does notneed to fill the large capacity of the lungs to provide a therapeuticeffect.

While it will be preferred not to inhale the therapeutic gas, the gasesare not toxic and some passage of the gasses into the trachea and/orlungs will not significantly detract from the therapy. Moreover, withpractice, many patients will be able to continue breathing ambient airthrough a nasal or oral route while simultaneously infusing the oral ornasal mucous membranes with the therapeutic gas. That is, in some cases,the patient may continue breathing through the mouth while infusing thenasal passages with the therapeutic gas or continue breathing throughthe nose while infusing the oral cavity with the therapeutic gas. Thus,in the first aspect of the present invention, the patient is requiredonly to limit or inhibit passage of the therapeutic gas into the tracheaand/or lungs in order to localize or concentrate the therapeutic gas inthe nasal or oral passages being treated.

In particular embodiments, the therapeutic gas may comprise essentiallypure carbon dioxide. By “essentially pure,” it is meant that the carbondioxide, or other therapeutic gas, is free from the significant presenceof other gases, i.e., the total volume of gas will comprise at least 50%carbon dioxide, preferably at least 70% carbon dioxide, and morepreferably 95% or greater. In addition to being free from other gases,the carbon dioxide will be free from other physiologically orbiologically active components, such as drugs, surfactants, and othersubstances that, although present at relatively low concentrations,would have physiologic or biologic effect.

In other embodiments, however, the carbon dioxide, or other therapeuticgas, may be present in a carrier which would have a significantpresence, i.e., the total volume of carbon dioxide will comprise atleast 6% carbon dioxide, preferably at least 30% carbon dioxide, andmore preferably 49%. The carrier may be inert or biologically active.Exemplary inert carrier gases include nitrogen, air, oxygen, halogenatedhydrocarbons, and the like. In preferred embodiments, the therapeuticgases are generated at a flow rate in the range from 1 cc/sec to 20cc/sec, preferably from 2 cc/sec to 10 cc/sec. For pediatricapplication, flow rates less than 1 cc/sec (e.g., 0.5 cc/sec) may bepreferred. Infusion preferably comprises directing the flow oftherapeutic gas into one nostril and allowing the flow to infuse throughthe nasal passages and pass outwardly through the other nostril. Suchinfusion will occur under the pressure of the therapeutic gas that isbeing released into the one nostril, i.e., the patient is not inhalingor otherwise causing the therapeutic gas to infuse through the nasalpassages. In such nasal passage infusion protocols, the patient's mouthis closed in order to block exit of the gas through the mouth. In analternative infusion protocol, the therapeutic gas is directed into thepatient's mouth and allowed to exit through either or both nostrils. Instill another infusion protocol, the therapeutic gas is directed into anostril or both nostrils and exits through the open mouth. In the lattertwo protocols, both the oral mucous membranes and nasal mucous membranesare infused with the therapeutic gas. The patient should avoid breathingsubstantially through the oral or nasal passages being perfused with thetherapeutic gas. It should be recognized that the patient can breathethrough the mouth while perfusing the nasal passages, and can breathethrough the nose while perfusing the oral cavity. Furthermore, thepatient can take single breaths during a long infusion step withoutsubstantially changing the total infusion time in that step.

The treatment steps may occur as a single infusion or multipleinfusions. The length of any particular infusion step will depend, amongother things, upon the degree of relief the patient is experiencing,i.e., the patient may continue and/or repeat infusions until relief isachieved. Single infusion steps usually will be performed for a time inthe range from 1 second to 20 seconds for rhinitis relief and 1 secondto 60 seconds for headache relief, and more usually from 2 seconds to 15seconds for rhinitis and 10 seconds to 30 seconds for headache. Theinfusing steps often will be repeated one, two, three, four, or moretimes in order to achieve the desired total treatment time set forth inthe table above. Usually, methods will be performed with hand-held orother delivery devices which have an adjustable flow rate capability.That is, the devices may be adjusted to deliver relatively constanttherapeutic gas flows at a particular value within the range from 1cc/sec to 20 cc/sec. The methods may thus further comprise adjusting thegas flow to a level which the patient perceives is comfortable. Afterthe gas flow is adjusted, a total duration of treatment may bedetermined based on the gas flow and the desired total amount of gas tobe delivered. While such treatment flows and treatment times mayinitially be selected based on data, such as provided in Table I above,it will be appreciated that the patient will eventually learn whattreatment flow rates, treatment times, and number of treatments lead tosuccessful symptom relief for them personally. Indeed, in medicalpractice today, gas therapy is a “titrate to effect” therapy without aspecified dosage.

A second aspect of the present invention comprises methods forgenerating a therapeutic dosage of carbon dioxide or other treatmentgas. The methods comprise releasing from a hand-held dispenser a flow oftherapeutic gas comprising from 1 cc/sec to 20 cc/sec of carbon dioxide.Preferably, the gas flow will consist essentially of carbon dioxide,i.e., be pure carbon dioxide as described above. Alternatively, however,the gas flow may comprise carbon dioxide present in a carrier gas, alsoas described above and/or with solid or liquid drugs or othersubstances. The hand-held dispenser will have an outlet suitable fordelivering the gas to the patient. In a preferred embodiment, the outletwill be suitable for sealing in or against a human nostril. In analternative embodiment, the outlet will be suitable for sealing in oragainst a human mouth. In another alternative embodiment, the outletwill be suitable for sealing around a human eye or both eyes. One ormore treatment steps may be performed, with each step having a durationin the range from 1 second to 100 seconds, preferably from 2 seconds to30 seconds, and often from 1 second to 20 seconds, depending on thecondition being treated and on its severity. The total number oftreatment steps will be selected depending on symptom severity.Typically mild symptoms require 1 or 2 treatment steps, moderatesymptoms require 2 to 3 treatment steps, and severe symptoms require 3to 8 treatment steps. The total number of treatment steps will beselected depending on the flow rate in order to provide a total targetdosage of the carbon dioxide. Typically, the flow rates will beadjustable to a set point within the range from 1 cc/sec to 20 cc/sec.While such treatment flows and treatment times and number of treatmentsteps may initially be selected based on data, such as provided in TableI above, it will be appreciated that the patient will eventually learnthe treatment regimen that leads to successful symptom relief for thempersonally.

In yet another aspect, the present invention comprises dispensers fordelivering therapeutic gases to a patient. The dispensers comprise acontainer holding a volume of the therapeutic gas, typically carbondioxide or any of the other therapeutic gases described above. Thedispenser further comprises a flow regulator that releases a flow of thetherapeutic gas from the container to an outlet that is adapted to sealagainst a human nostril, mouth, or eye. Thus, the dispensers will beuseful for delivering the therapeutic gas to the nostril, mouth, or eyefor infusion of a mucous membrane according to the methods generallydescribed above. As in the methods described above, the therapeutic gasis preferably carbon dioxide, either substantially pure carbon dioxideor carbon dioxide present in a carrier gas or liquid and/or combinedwith other active or non-active substances. The flow regulatorpreferably will be adjustable so that the patient can select a flow ratein the range from 1 cc/sec to 20 cc/sec, or within the other ranges setforth above. In an exemplary embodiment of the dispenser, the containercomprises a cylinder, the adjustable flow regulator comprises a turnablecap at one end of the cylinder, and the outlet comprises a nozzle in thecap. The regulator may be turned to open the dispenser and initiate aflow of the carbon dioxide or other therapeutic gas. By thenappropriately turning the cap, the flow rate can be adjusted to theuser's preferred rate, and the outlet then inserted into or around theappropriate patient's orifice, in order to initiate infusion accordingto the methods described above.

In a further aspect, dispensers of the present invention for deliveringcarbon dioxide to a patient comprise a container holding a volume ofcarbon dioxide under pressure. A flow regulator is provided on thecontainer and releases a flow of carbon dioxide from the container at arate in the range from 1 cc/sec to 20 cc/sec. Preferably, the dispenserfurther comprises an outlet, where the outlet may be adapted to sealagainst a human orifice. Usually, the carbon dioxide will besubstantially pure, although in other cases may be present in a carriergas or liquid or in combination with other active or non-activesubstances. In certain particular embodiments, the carbon dioxide ispresent in the container as a liquid, wherein relatively large volumesof carbon dioxide can be stored. In other instances, the carbon dioxidewill be present in the container as a pressurized gas. While the latterdispensers will hold less carbon dioxide, they do not need to be assturdy as the containers that hold liquid carbon dioxide at much higherpressures. Preferably, the flow regulators will be adjustable to setpoints within the flow rate range.

In yet another aspect, kits according to the present invention comprisea container holding a therapeutic gas and instructions for use settingforth any of the methods described above for delivering the gas to apatient. The container may comprise any of the preferred dispensersdescribed above, and the instructions for use and container will usuallybe packaged together in a conventional medical device package, such as atube, tray, pouch, box, or the like.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a hand-held gas dispenser constructed in accordancewith the principles of the present invention.

FIG. 2 is an axial cross-sectional view of an initial embodiment of thedispenser of FIG. 1.

FIGS. 3A-3C are detailed cross-sectional views of the dispenser head andflow regulator of the dispenser of FIGS. 1 and 2.

FIGS. 4A and 4B are detailed illustrations of the flow regulator needleof the dispenser head, showing exemplary dimensions for the initial andpreferred needle configurations respectively.

FIG. 4C illustrates the analytical relationship between the criticalneedle taper angle α and the size of the annular orifice d for a needledisplacement x.

FIG. 5 is a detailed view of the penetrable cap positioned in thepressurized gas container of the dispenser of FIGS. 1 and 2, shown afterpenetration by the needle of FIG. 4A.

FIG. 6 illustrates a preferred embodiment for calibrating the flowregulator of FIGS. 3A-3C.

FIG. 7 is a cross-sectional view taken along line 7-7 of FIG. 6.

FIG. 8 is a cross-sectional view taken along line 8-8 of FIG. 7.

FIG. 9 is a schematic illustration of a hand-held gas dispenserconnected to a large gas supply source.

FIG. 9A illustrates an alternative construction for a dispenser headhaving separate puncture and flow-regulating means.

FIG. 9B illustrates a preferred two-piece dispenser head embodiment.

FIG. 10 illustrates an alternative hand-held dispenser employing arelatively low pressure gas source.

FIGS. 11 and 12 illustrate another alternate embodiment of the dispenserof the present invention, illustrating a chemical-gas generation systemfor producing gas according to the methods of the present invention.

FIG. 13 illustrates a patient employing the dispenser of FIG. 1 fortreatment of symptoms associated with common ailments.

FIG. 14 illustrates a kit constructed in accordance with the principlesof the present invention.

FIG. 15 is a graph comparing flow rate control sensitivity achieved withdifferent needle designs.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

1. Treatment of Allergic Rhinitis and Headache. It has been found by theinventors, that bathing the mucous membrane of the nose, nasal passages,and mouth, with gaseous carbon dioxide for times as short as one secondcan suppress the onset of acute irritation of the mucosa caused bytriggers such as airborne and contact-transmitted allergens and/orantigens. Furthermore, chronic inflammation of the mucosa and associateddistress, caused by extended exposure to allergens and/or antigens, maybe relieved within a few minutes by repeating such carbon dioxideapplications. A possible mechanism of action of the above describedlocal carbon dioxide treatment is the following. Creating a highconcentration of carbon dioxide (hypercapnia) by infusing it into thenasal passages causes a very fast lowering of the pH (making moreacidic) of the mucous membranes depressing the neuronal activity(inhibiting inflammatory mediator release such as histamine) of thenerves that supply the nasal mucous membranes and connect directly tothe brainstem. Asthma is known to be a comorbid disease to allergicrhinitis. Carbon dioxide is known to relax both central and peripheralairways in asthmatic adults. In addition, it is known that oxygenationis improved in patients with status asthmaticus, chronic obstructivepulmonary disease, and bronchiolitis by inhalation of helium. Also,inhaled nitric oxide improves the oxygenation and ventilation of mostchildren with acute, hypoxic respiratory failure. For this reason, theserespiratory ailments can be reduced or relieved by administering theabove-described treatment using carbon dioxide or helium or nitricoxide. Furthermore, headaches (e.g., migraine headaches, tension-typeheadaches, cluster headaches, jaw pain, facial pain) are thought to bedue to triggers creating a hyperexcitability state of nerves releasinginflammatory mediators such as histamine and serotonin. For this reason,headaches can be reduced or relieved by administering theabove-described carbon dioxide treatment. Epilepsy, also a nervoushyperexcitability state, is known to be a comorbid disease to headachesand antiepileptic medications are used for migraine prevention. For thisreason, epilepsy can be reduced or relieved by administering theabove-described carbon dioxide treatment. A convenient hand-held easilycontrolled dispenser of carbon dioxide has been found to be an adequateand optimum means for practicing this carbon dioxide applicationprocess. Furthermore, other gases such as nitric oxide, oxygen, helium,and others may be administered similarly as therapeutic gases via theconvenient hand-held easily controlled dispenser.

Essential elements of successful suppression of irritating symptoms,pain, and inflammation through use of carbon dioxide are the convenientdispensing of the carbon dioxide or other therapeutic gas at a time, ata controlled flow rate, and for a duration selected by the user. Becauseof the ability of carbon dioxide to quickly or immediately suppress anacute attack, the means for carbon dioxide application should beavailable immediately, upon demand by the user, at the time whenirritating symptoms appear upon exposure to a trigger. If circumstancesdo not permit such immediate application, the means for application mustbe available continuously to relieve the consequent inflammation anddistress as soon as possible after the exposure when circumstancespermit its use.

Furthermore, it is desirable that the user be able to conveniently butprecisely and controllably select a rate and duration of carbon dioxideflow that lies between the lower limit of effectiveness and the upperlimit of tolerance. It has been found that these limits are subjective,depending upon the personal sensitivities of the individual user, thedegree and extent of the user's irritant reaction, and the site ofcarbon dioxide injection. Flows as low as 1 cc/sec for 1-2 seconds intothe nose are effective for suppression of onset of acute allergicsymptoms, whereas flows of 4-5 cc/sec for 5-10 seconds are typicallyselected for optimum relief from a mild chronic allergy attack. Forseverely inflamed mucosa and/or for injection into the mouth, flows ashigh as 10 cc/sec or higher for as long as 15 seconds or longer oftenare selected for optimum relief. For the treatment of tension andmigraine headaches, the flow durations can be substantially longer, asgenerally set forth in the Dosage Guideline (Table I) above.

At low flow rates, the presence of the carbon dioxide produces a“tingling” sensation similar to that produced during drinking ofcarbonated beverages that inadvertently enter the nasal passages e.g.,“bubbles up the nose”. This is the effective rate and the tingling is awelcome sensation because it usually coincides with immediate relief ofsymptoms. Above a certain subjectively determined flow rate thesensation becomes unpleasant, which may be described as a “stinging” or“burning” sensation. At a still higher flow rate (maximum tolerablerate), the stinging sensation becomes intolerable and subjects removethe device from their nostril. It has been found that, for a fewindividuals, this tolerance level can be as low as 1-2 cc/sec for asecond or less of injection into the nose. More typically, an injectionrate of up to 10 cc/sec can be tolerated for 5 seconds or more into thenose by most users and into the mouth by almost all users. It must benoted, however, that the tolerance level depends strongly on thesequential phase of the application and on the degree of inflammationand/or pain at that phase. The tolerance level generally is lower (e.g.,<3 cc/sec typically) at the onset of the first carbon dioxide injection,especially when there has been chronic inflammation and/or pain. After afew seconds the tolerance level rises substantially to the levelsalready discussed. In fact, the “stinging” sensation is described as awelcome immediate relief to the “tickling” sensation that causessneezing and other distress during an allergy attack, i.e., analogous torelieving an itch by scratching a skin irritation. Similarly, the“stinging” sensation is described as a welcome immediate relief to the“pressure” sensation that causes pain and other distress during aheadache attack.

Accordingly, the range of effective and tolerable flow rates of carbondioxide is between 1 cc/sec and 20 cc/sec, preferably between 1 cc/secand 10 cc/sec, and most preferably between 2 cc/sec and 10 cc/sec. Thecarbon dioxide flow is preferably regulated easily, controllably, andwith rapid response within this range of flow rates by the user.

Most often the major site of general distress is the head, for which thepreferred mode of carbon dioxide injection is directly into a nostril.While not inhaling the carbon dioxide, carbon dioxide is injected into anostril and continued until full relief is obtained. This usually occurswhen the carbon dioxide flow is detected exiting the opposite nostriland/or the mouth. With an allergy attack, often the nasal passages areblocked by swelling of the mucosa, in which case sufficient pressureautomatically builds to open and perfuse the passage through eachnostril separately. When both passages are clear, each can be perfusedseparately by holding one nostril closed while opening the mouth, orboth can be perfused by closing the mouth and allowing the flow into onenostril to exit through the other. Frequently inflammation, swelling,and itching of the upper mouth accompany the irritant reaction to theallergen and/or antigen. In this case, it is most effective to injectthe carbon dioxide through pursed lips directly into the mouth with exitthrough the nose while the breath is held. Specific techniques may belearned by experience and optimum procedures will depend on personalpreference. The ability of the patient to optimize the treatmentprotocol is enabled by the fully adjustable flow rate and selectableinjection site afforded by the devices of the present invention.

2. Initial Dispenser Embodiment. FIGS. 1-5 illustrate an initialdispenser embodiment 10 that was designed, built, and tested, with testresults shown below. A subsequent presently preferred dispenserembodiment, having similar basic function but with improvements asdescribed in Section 4 below, also was designed, built, and tested, withtest results shown below. In the initial dispenser embodiment, a carbondioxide cartridge housing 12 has screw threads 14 on the neck 15 of thecartridge. Such threaded carbon dioxide cartridges presently aremarketed for use in other applications (available from Leland Limited,Inc., South Plainfield, N.J.), although the contents of such presentcarbon dioxide cartridges have not been qualified for administration tohumans. The threaded carbon dioxide cartridge 12 is screwed into athreaded dispenser head 16, containing a perforating and flow-regulatingneedle 18 and flow dispensing ports 20. The threads employed, 28 perinch (11 per cm), are those commonly employed in commercial threadedcartridges.

The configuration of the initial dispenser embodiment as shown in FIGS.1-5 provides an acceptable degree of flow regulation with acceptably lowleakage through the valve seat formed by its penetration of thecartridge sealing cap. A hardened steel needle having the size and shapeshown in FIG. 4A is sharp and strong enough to penetrate a plug-type cap30 sealing the neck 15 of cartridge 12. Several designs of caps arecomposed of mild steel and are employed in commercial cartridges meetingindustry safety standards, one of which is shown as the plug-type cap 30in FIGS. 2,3,5 and 7. The cartridge and cap design features meetingthese standards, including the required wall thickness and materialstrength of the cartridge and cap walls, are well known to those skilledin high pressure gas cartridge design, and have been widely accepted asbeing fully adequate for many years in mass-produced consumer products.Needle 18 having the dimensions set forth below, when employed with caps30 having the critical dimensions set forth below, will provide bothleak tight seals and optimum flow rates for the present invention. Asshown in FIG. 3B, when the needle-bearing head 16 is fully screwed ontothe carbon dioxide cartridge, the end of the cartridge encounters thesurface in which the needle is mounted or another limit. The distancethat the needle can penetrate the sealing cap 30 thereby is preciselylimited, and the hole it thereby produces has precisely defineddimensions which control and limit the rate of carbon dioxide flow fromthe cartridge to within a desired flow range (e.g., 1-20 cc/sec) forsafe and effective application. The needle 18 creates a pressure-typevalve seat as it enters and penetrates the cap. A stop or limit, e.g.,provided by engagement of the head 16 against the neck 15, prevents theneedle from distorting or enlarging the seat (hole). Controlled flowoccurs when the needle is controllably withdrawn from the seat, as shownin FIG. 3C.

It has been found that mounting the needle 18 in a head 16 material witha relatively high degree of elasticity, such as a plastic polymer,provides a degree of compliance sufficient to accommodate any off-axis“wobble” that occurs during rotation of the head and thereby avoids theassociated non-circular and leaky penetration hole that occurs when theneedle is mounted rigidly in a metal head. The elastic mount alsoprovides compressive compliance that keeps the needle firmly seatedafter its repeated insertion into the orifice.

The configuration of the dispenser embodiment shown in FIGS. 1-5, havingthe carbon dioxide-containing cartridge screwed directly into thedispenser head, provides additional advantages. The amount of carbondioxide contained in a convenient hand-held dispenser is thereby greatlyincreased over configurations that employ an external cartridge housing.Commercially produced cartridges with threaded necks are available invarious sizes containing 8, 12, 16, 38 or more grams of carbon dioxide.The appropriate size employed in the dispenser embodiments describeddepends on the relative importance of cartridge size and number oftreatment doses required for a particular use. For example, studies haveshown that hand-held products for treatment of allergic rhinitis mustprovide hundreds of doses, which would require a relatively large carbondioxide cartridge. In contrast, hand-held products for treatment ofheadache need to provide only a few doses, requiring a relatively smallcartridge. Balanced against these requirements is the relativeimportance of size depending on the preferences of various users, e.g.,for convenient carrying of the dispenser in a purse or pocket. The16-gram size cartridge is a presently preferred compromise among thesefactors. The options readily available for head and cartridge designshaving a standard thread in the embodiments described provide a highdegree of design flexibility. Similarly, the relatively high simplicityand easy producibility of the dispenser head embodiments describedpermits fabrication of the dispensing head and cartridge as a singledisposable device, especially with a molded plastic polymer head.

The dispenser 10 can be conveniently operated using the stepsillustrated in FIGS. 3A-3C. In FIG. 3A, the dispenser head 16 is shownin its “shelf” condition where the head is fully elevated relative tothe cartridge body 12 so that needle 18 lies above the exposed surfaceof cap 30. At this point, of course, the cap 30 has not been perforated.It will be appreciated that the head 16 may be completely removed and,indeed, the head 16 and cartridge 12 may be stored and/or distributedseparately, where the head 16 may be disposable or reusable. When apatient desires to begin using the dispenser 10, the head 16 will berotated in the direction shown by arrow 40 in FIG. 3A to cause the head16 to lower relative to the cartridge body 12 and to cause needle 18 topenetrate into cap 30, as shown in FIG. 3B. By completely closing thecap 16 against the upper surface of the neck 15, as shown in FIG. 3B,the needle 18 will precisely define the penetration 42 having thedesired geometry (defined by the geometry of the needle), as shown inFIG. 5. The dispenser 10 is then ready for use. Alternatively, thedispenser can be supplied with the needle having penetrated the cap. Inthis manner, quality control sampling of the contained gas can beperformed at the manufacturing plant by twisting the dispenser head. Auser can open the dispenser head 16 by rotating in the oppositedirection, as indicated by arrow 42 in FIG. 3C. The dispenser head isrotated sufficiently to lift the needle 18 up out of the penetration 42and cap 30. The degree to which the needle is removed from thepenetration 42 will determine the flow rate of the gaseous carbondioxide or other therapeutic gas. That is, the gap left between theouter surface of the needle 18 and the inner surface of the penetration42 will be variable to create a variable annular flow area through whichthe gas can pass. The gas flow rate will thus depend on the degree towhich the cap 16 has been rotated.

Referring now to FIGS. 6-8 the dispenser 10 may be modified to have acalibrated dispensing head 16′ with numbers 50 printed or engraved onits lower end to indicate flow rate set points. In a first embodiment,the numbers could be provided without further modification of the head16 so that a user can dial in any flow rate at or between the designatednumbers. In a second embodiment, the dispenser head 16′ will be modifiedto have a spring arm 52 which is received in a plurality of detents 54formed in the collar 94. The locations of the detents 54 are selected sothat the dispenser head 16′ will “click” into place for each of the setpoints indicated by numbers 50 on the dispenser head. To utilize thedispenser head 16′, the user will turn the cap in the direction of arrow56 until the flow rate number 50 is aligned with an indicator arrow 58printed or embossed on the cartridge body 12. In addition to the visualalignment, the user will sense and hear when the spring arm 52 hasentered the detent 54 that corresponds to the desired flow rate. In themost preferred embodiments, a notch 60 is formed in the collar 94. Thenotch 60 acts as a rotation-limiting stop so that the user cannotaccidentally remove the dispenser head 16′. That is, as the spring arm52 is rotated in the direction of arrow 56 it will eventually enter thenotch 60. The abrupt wall 62 at the end of the notch will preventcontinued rotation, in turn preventing accidental removal of the head.Of course, the presence of the spring arm 52 may prevent reuse of therotational cap 16′, so that the design of FIG. 6-8 will generally beintended to be disposable.

It should be apparent that methods other than rotation of the dispenserhead can be used to controllably vary the flow through a perforationorifice; e.g., the needle can be moved axially by a lever arrangement tocontrollably accomplish the described perforation and flow regulationwithin the preferred range of flow rates described herein. Such anarrangement in a hand-held embodiment having a similar optimum degree ofsensitivity and range of adjustment by the fingers as the rotation meansdescribed herein can achieve the same result.

3. Embodiment with Separate Puncture and Flow Control Means. Referringnow to FIG. 9A, an alternative dispenser head embodiment 80 will bedescribed. The dispenser head 80 is similar to the embodiment describedabove with respect to FIGS. 1-5, except that the needle perforation andflow regulating aspects of the assembly are separated. In particular,the dispenser head 80 comprises a lower collar 82 and a flow-regulatingcap 84 threadably mounted to an upper end of the lower collar. Needle 86is secured in the lower portion of the flow-regulating cap 84 andincludes two tapered regions. The first tapered region 88 acts as theneedle tip which penetrates seal 90 which is mounted over the upper end92 of a high pressure gas bottle 94. The seal 90 extends above athreaded neck 96 of the gas bottle 94. The lower collar 82 is threadablymounted over the threaded neck 96 in such a way that the seal 90 extendsinto a high pressure gas chamber 98 within the upper end of the lowercollar 82. An O-ring seal 100 is provided to inhibit leakage of the highpressure gas.

Flow regulation in the dispenser head 80 is provided by the secondtapered region 102 which is received in a valve seat 104 formed in theupper end of the lower collar 87. Rather than relying on needlepenetration to form the flow control aperture, dispenser head 80 relieson a pre-formed conical valve seat 104 which mates with the taperedregion 102 on the needle. In this way, the dimensions of both the seat104 and the tapered region 102 may be carefully controlled in order toassure accurate gas flow control. Thus, when the flow regulating cap 84is twisted to raise the cap relative to lower collar 82, the taperedregion 102 will be lifted out of the valve seat 104. In this way, theflow regulation of the gas can be controlled. Additionally, sealing ofthe gas flow when the cartridge is to be turned off is provided by bothseating of the tapered needle portion 102 in the seat 104 as well asseating of the needle tip in the penetration created in the seal 90. Theuse of the valve seat 90, which can be formed from a conventional hardmetal, ceramic, or other valve material, can greatly enhance the usefullife of the dispenser head 80. Thus, such designs may be particularlyvaluable for non-disposable units where the dispenser head 80 can bereused. Of course, the associated gas cartridge will be replacedwhenever the gas being carried has been depleted.

4. Preferred Dispenser Embodiment. From the tests with the initialdispenser embodiment, several improvements were defined leading to apreferred embodiment that also was constructed and tested. It was foundthat the preferred dispensers of the present invention should enableprecise but easy control of the flow rate over the desired flow rangesin a convenient hand-held configuration. In the specific preferredembodiment illustrated in FIG. 9B, it has been found that there is anoptimum relationship between the rate of flow of carbon dioxide or othertherapeutic gas selected by a user and the degree of rotation of thedispenser head relative to the cartridge that is required to obtain thatflow. If the degree of rotation required is too small, it is difficultfor the user to select the optimum rate of flow, i.e., the adjustmentsensitivity is too coarse. If the degree of rotation is too large, theadjustment to the optimum flow rate requires more than one positioningof the thumb and forefinger that the typical user employs to rotate thehead; i.e., the adjustment is awkward and its sensitivity is greaterthan required. In the latter respect, the mode of adjustment employed bymany if not most experienced adult users is to hold the dispenser in thepalm of one hand only with the third, fourth and fifth fingers and torotate the dispenser head with the thumb and index finger of that hand.

Specifically, it has been found that the rotation of the dispenser headof the preferred embodiment required to obtain the maximum flow rateemployed by most users, e.g., 10 cc/sec, should not and need not exceedabout 120 degrees in order to obtain an entirely adequate sensitivity ofadjustment and to not exceed the rotation comfortably obtainable with acontinuous motion of the thumb and index finger. Conversely, a degree ofrotation to obtain such typical maximum flow rate, if less than about 30degrees, is too coarse for sensitive adjustment of the flow over the1-10 cc/sec range of typical optimum flow rates defined previously. Itshould be apparent that the optimum relationship between flow rate anddegree of head rotation can be obtained by selecting appropriatecombinations of perforation orifice size, head diameter and fineness ofthreads on the cartridge (number of threads/inch).

In using the needle having the initial configuration shown in FIG. 4A itwas found that an axial movement of the needle of only about 0.001 inchvaries the gas flow from zero to the maximum required flow of 20 cc/sec.This corresponds to a dispenser head rotation of only about 10 degreesusing the standard 28 threads per inch on commercial gas cartridges.While this arrangement gave acceptable flow adjustment for the initialtests, the 10 degree rotation is far less than the optimum rotation of30 to 120 degrees defined above. Accordingly, an alternative dispenserhead embodiment permitting use of finer threads, and an alternativeneedle configuration permitting a much larger axial motion, wereincorporated into the preferred dispenser embodiment shown in FIG. 9B. Apreferred feature of the subject invention, therefore, is the shape andsize of the needle, and the extent and means for precise production andreliable repeated resealing of the perforation orifice by the needle, toobtain the optimum controllable flow rates in the defined effective andtolerable ranges.

The preferred dispenser embodiment shown in FIG. 9B retains the majorfeatures of the initial embodiment described previously but, inaddition, it can be seen that the single dispenser head part of theinitial embodiment has been replaced by a two-part assembly consistingof a head 16′ and a collar 94. The head 16′ is similar to the initialdispenser head 16 in that it incorporates a perforating andflow-regulating needle 18′ along with ports 20′ for delivering thedispensed gas. The collar 94 is screwed onto the carbon dioxidecartridge neck 15′ and fixed there against rotation, e.g. by a jamthread 14′. The head 16′ is screwed onto a fine thread 96 on the collar.The fine thread 96 (e.g., 48-56 threads/inch) permits a much finerrotational adjustment than the coarse thread 14′ (typically 28threads/inch) on the cartridge neck.

The preferred needle configuration, shown in FIG. 4B, permits obtainingthe required very small change in orifice area by a relatively largeaxial displacement of the needle. The lower most portion of the needle,over a distance approximately equal to the thickness of the cartridgesealing cap 30, has essentially the same shape and size as the puncturepoint 97 shown in FIG. 4A as employed in the initial embodiment of thedispenser. The configuration of this point is an optimum compromisebetween the strength of a blunt point and the reduced force requirementof a sharp point in the puncture process. However, the needle region 98′beyond the puncture point, that is adjacent to the perforated cap wall,determines the size of the annular flow-controlling orifice of the valveseat 42 when the needle is partially withdrawn. The configuration of theflow-controlling seat region 98′ of the needle is advantageous forobtaining the required flow regulation characteristics of the dispenser.

As shown analytically in FIG. 4C, the axial needle displacement giving arequired size of the flow-controlling annular orifice is inverselydependent on the taper angle α of the needle in the seat region. Thistaper angle α is approximately 20 degrees in the initial needleconfiguration shown in FIG. 4A, which required a needle displacement xof about 0.001 inch between zero flow and full flow as obtained by a 10degree rotation of the head with 28 threads/inch. To obtain the 120degree optimum head rotation, the needle seat taper angle α thereforemust be about 1.7 degrees for 28 threads/inch or about 3 degrees for thepreferred 48 threads/inch.

Accordingly, exemplary dimensions for the needles 18 and 18′ and cap 30are set forth in Table II below and provide for desired flow rates inthe range from 1 cc/sec to 20 cc/sec for cartridges 12 holding liquidcarbon dioxide under pressure. It should be apparent that the preferredneedle configuration shown in FIG. 4B, and the calibration and detentprovisions shown in FIGS. 6-8, can be used with either the one-piecedispenser head shown in FIGS. 3A-3C and FIG. 7 or with the two-piecedispenser head shown in FIG. 9B to obtain its attendant advantages. Italso should be noted that the two-piece preferred embodiment does notrequire detent slots in the cartridge threads 14′, but only in thecollar threads 96.

TABLE II EXEMPLARY NEEDLE AND CAP DIMENSIONS Range Specific Needle 18:(FIG. 4A) W 0.4-0.6 mm 0.50 mm α 15-25 deg   20 deg L₁ 0.4-0.6 mm 0.37mm L₂ 0.4-0.6 mm 0.37 mm Needle 18′: (FIG. 4B) W₁ 0.4-0.6 mm 0.50 mm α₁2-6 deg  3.0 deg L₁′ 0.6-1.0 mm 0.75 mm L₂′ 0.2-0.6 mm 0.37 mm Cap 30:(FIG. 5) t 0.25-0.4 mm 0.30 mm Ø 3.03.8 mm  3.2 mm

5. Embodiment with Separate Puncture and Valve Seal Mechanism. Referringnow to FIG. 9A, an alternative dispenser head embodiment 80 will bedescribed. The dispenser head 80 is similar to the embodiment describedabove with respect to FIGS. 1-5, except that the needle perforation andflow regulating aspects of the assembly are separated. In particular,the dispenser head 80 comprises a lower collar 82 and a flow-regulatingcap 84 threadably mounted to an upper end of the lower collar. Needle 86is secured in the lower portion of the flow-regulating cap 84 andincludes two tapered regions. The first tapered region 88 acts as theneedle tip which penetrates seal 90 which is mounted over the upper end92 of a high pressure gas bottle 94. The seal 90 extends above athreaded neck 96 of the gas bottle 94. The lower collar 82 is threadablymounted over the threaded neck 96 in such a way that the seal 90 extendsinto a high pressure gas chamber 98 within the upper end of the lowercollar 82. An O-ring seal 100 is provided to inhibit leakage of the highpressure gas.

Flow regulation in the dispenser head 80 is provided by the secondtapered region 102 which is received in a valve seat 104 formed in theupper end of the lower collar 87. Rather than relying on needlepenetration to form the flow control aperture, dispenser head 80 relieson a pre-formed conical valve seat 104 which mates with the taperedregion 102 on the needle. In this way, the dimensions of both the seat104 and the tapered region 102 may be carefully controlled in order toassure accurate gas flow control. Thus, when the flow regulating cap 84is twisted to raise the cap relative to lower collar 82, the taperedregion 102 will be lifted out of the valve seat 104. In this way, theflow regulation of the gas can be controlled. Additionally, sealing ofthe gas flow when the cartridge is to be turned off is provided by bothseating of the tapered needle portion 102 in the seat 104 as well asseating of the needle tip in the penetration created in the seal 90. Theuse of the valve seat 90, which can be formed from a conventional hardmetal, ceramic, or other valve material, can greatly enhance the usefullife of the dispenser head 80. Thus, such designs may be particularlyvaluable for non-disposable units where the dispenser head 80 can bereused. Of course, the associated gas cartridge will be replacedwhenever the gas being carried has been depleted.

6. Alternative Gas Provision Means. Referring now to FIG. 9, the methodsof the present invention may also be performed with high volume systemsin clinical, institutional, and chronic home-care settings. A largevolume carbon dioxide or other gas bottle is provided and connectedthrough a conventional pressure regulator 72. The output of the pressureregulator 72 will preferably pass through a gas-flow meter 74 and beconnected by a suitable hose or tubing 76 to a hand-held dispensernozzle 78. The nozzle 78 will have an outlet 79 adapted to interfacewith a nostril or mouth as described above for the hand-held embodiment.The nozzle 78 will typically also include a flow control valve, whichmay be essentially as illustrated in the earlier embodiments for thehand-held dispensers. The only difference required would be that,instead of being connected to a small carbon dioxide or other gascartridge, the nozzle 78 may be connected to a much larger gas bottle 70through flexible tube or hose 76, optionally with an in-line flow meterwhich allows the user to select and adjust a desired flow rate.

As described thus far, the embodiments of the dispensers of the presentinvention have relied on high pressure systems which contain liquidcarbon dioxide or other therapeutic gas. Low pressure systems may beassembled in at least two ways. As shown in FIG. 10, a first exemplarylow pressure system 120 may comprise a thin-walled container 122 whichcontains gaseous carbon dioxide or other therapeutic gas at a relativelylow pressure, e.g., 100 psi. The containers 122 may be of the typeconventionally employed for low pressure spray cans available for avariety of consumer uses. In contrast, the high pressure carbon dioxidecartridges described above will usually have an internal pressure ofabout 1,000 psi. The low pressure container 122 may be combined with adispenser head 124 constructed generally as described above. The sizesof the flow passages, however, might be modified in order to accommodatethe lower source pressures. In a second embodiment 140 carbon dioxideand other therapeutic gases may be provided at low pressures using achemical generation system, as shown in FIGS. 11 and 12. For example, acontainer 142 may include reagents which, upon mixing, release carbondioxide. In a particular embodiment, dry citric acid powder and sodiumbicarbonate are disposed in the container 142 with separated water. Thewater is then mixed with the dry components, typically by crushing thecontainer 142, as shown in FIG. 12. The water can be released in avariety of ways. For example, the water could be separated by afrangible barrier between the water and the dry components. Preferably,the water will be contained in frangible water-containing microcapsulesso that the water is liberated as the container is crushed. The amountof water liberated, however, will depend on the degree to which thecontainer 142 has been crushed, allowing a relatively long useful lifefor the system. As with prior systems, a dispenser head 144 having flowpassages capable of selectively controlling the flow rate to the patientwill be provided.

7. Description of Use of the Dispenser Embodiments. Referring now toFIG. 13, any of the dispensers described above may be utilized bydelivering the carbon dioxide or other therapeutic gas to the patient,either through the nose or through the mouth. As shown in FIG. 13, thedispensing head 16 of dispenser 10 is placed by the patient P into onenostril, while the patient refrains from inhaling the therapeutic gas,e.g., holds his/her breath. The carbon dioxide or other therapeutic gasfrom the dispenser 10 will thus infuse into the nostril, upwardly intothe nasal passages and outward through the other nostril, preferablywhile the patient refrains from inhaling the therapeutic gas. Usually,the patient will keep his/her mouth closed during the nasal infusion,thus limiting the volume of the gas that infuses downward and throughthe mouth. In some instances, however, it may be desirable for thepatient to open his/her mouth (while continuing to refrain from inhalingthe therapeutic gas) so that the carbon dioxide or other therapeutic gasinfuses not only through the nasal passages but downward through thethroat and outward through the mouth. In this way, the mucous membranesof the nasal passages as well as the upper regions of the throat will betreated.

In other embodiments, the user may place the cartridge 10 into his/hermouth, permitting the carbon dioxide or other therapeutic gas to infuseupwardly through the throat and outward through the nostrils. Again, thepatient will generally refrain from inhaling the therapeutic gas so thatthe treatment gas does not enter into the trachea or lungs. By limitingthe regions being treated to the nasal passages and in some instancesthe nasal passages and upper regions of the throat, only very smallvolumes of the gas are required for treatment, and high (unbreathable)concentrations of the gas can be more effectively employed. This isparticularly advantageous when hand-held systems are used where theamount of carbon dioxide or other treatment gas is limited. As noted inthe examples provided below, it has been found that even very lowvolumes of carbon dioxide can be highly effective in treating a numberof symptoms associated with the common ailments described above.

As shown in FIG. 14, kits according to the present invention willinclude a carbon dioxide or other therapeutic gas dispenser 10 incombination with instructions for use 12. The instructions for use willinclude written instructions corresponding to any of the methods of thepresent invention as described above. In particular, the writteninstructions will refer specifically to use of the cartridge 10 in a wayto relieve symptoms of common ailments as described above. In additionto the cartridge 10 and written instructions 12, the kits will usuallyinclude packaging, for example in the form of a cylindrical container114 having a removable cap 116. The dispenser 10 and instructions foruse 112 will conveniently be packaged together within the container andcovered by the cap 116.

The following examples are offered by way of illustration, not by way oflimitation.

EXPERIMENTAL 1. Dispenser Models Constructed and Tested

Two models of the initial one-piece head embodiment shown in FIG. 2 wereconstructed and tested: one with the initial needle configuration shownin FIG. 4A and one with the preferred needle configuration shown in FIG.4B. Similarly, two models of the preferred two-piece embodiment shown inFIG. 9B (with 48 threads/inch) were constructed and tested: one with theinitial needle configuration shown in FIG. 4A and one with the preferredneedle configuration shown in FIG. 4B. The dispenser heads were machinedfrom Delrin plastic stock, with embedded needles machined from hardenedcarbon steel stock. Commercially available steel cartridges withthreaded necks (28 threads/inch), containing 16 grams of carbon dioxide,were used in all models. The configurations of the needles were thoseshown in FIGS. 4A and 4B, with a 3 degree taper in the seat region 98′of the preferred needle configuration.

FIG. 15 shows experimental measurements of the flow rate characteristicsfor the one-piece and two-piece embodiments with the initial needleconfiguration, as well as those for the combination of preferredtwo-piece dispenser head with the preferred needle configuration. Dataobtained using the initial needle configuration was too erratic to beplotted, i.e., having large hysteresis and other non-reproducible flowcharacteristics. The dashed lines show the general sensitivity of flowrate to head rotation for those models, however. It can be seen that thepreferred needle configuration 18′ gives the greatly improvedreproducible control and sensitivity required for self-treatment by thepatient. The one-piece embodiments of the device of the presentinvention described above were used in these experiments.

2. Preliminary Human Application Tests

A. Materials and Methods

Test Device

The test device was a hand-held, multi-dose, disposable, dispenser thatwas approximately 3 to 4 inches long and 6/8 to ⅞ inches in diameterconstructed as described above. The device consisted of a plastictwist-top flow regulator mounted on top of a pressurized steel cartridgecontaining liquid carbon dioxide. The tip of the flow regulator has anosepiece that is the optimal size and configuration to place againstand seal off a nostril for administration of the gas. In a number ofsubjects, the effective nasal and oral carbon dioxide flow rates, andmaximum tolerable nasal and oral flow rates, were measured using alaboratory apparatus. This apparatus consisted of a flow regulatorconnected via tubing to a flow meter and a large tank of carbon dioxide.These flow data were used, together with the number of seconds gas wasadministered during therapy, to calculate the estimated dose of gas inmilliliters.

Subjects

Of the total of 15 subjects included in the analysis, 11 used thetreatment for 35 headaches and 9 subjects used it for 9 allergy attacks.Three subjects treated both headache and allergy but on different days.The subjects included adults, elderly, and children of both sexes ingood general health, having mild, moderate, and severe headaches orhaving allergies to plant, animal, or airborne allergens. The device wasused to treat migraine and tension-type headaches, jaw pain, andallergies (allergic rhinitis, with symptoms that included sinuscongestion, sneezing, and itchy throat and eyes). There was nolimitation on the duration of symptoms before treatment with the device.Subjects with no prior use of the device and those who have used it (totreat allergy symptoms) previously were included.

Transmucosal Treatment

Carbon dioxide (100%) was administered nasally by the subject for a fewseconds via a nostril to fill the nasal passages while holding theirbreath, or taking breaths of room air occasionally if the dose waslengthy. The gas exited the other nostril. Such nasal administration issimilar to presently marketed nasal inhalers except that theadministered gas was not inhaled. Oral administration, via pursed lipswith carbon dioxide exiting via the nostrils, was found to be moreeffective for allergic inflammation extending into the oral cavity.Subjects took as many doses as they needed for relief. It is importantto note that there were no number of doses, duration of dose, timebetween doses, or gas flow rate specified for the user. Subjects chosetheir own regimen for symptom relief. Similarly, in medical practicetoday, gas therapy is a “titrate to effect” therapy without a specifieddosage.

Outcome Measures

The International Headache Society (IHS) divides headache intensity intothree categories: mild, moderate, and severe. The rating of theintensity level depends on the extent to which the headache interfereswith the ability to function. Mild headaches do not interfere with theability to function, moderate headaches interfere with the ability tofunction but do not require bed rest, and severe headaches areincapacitating and require bed rest. The IHS uses headache relief at twohours as its primary outcome measure for present-day headache drugstudies. Since therapy of the present invention acts much faster thanpresent-day drugs, the primary outcome measure selected for thisanalysis was headache relief at 30 minutes. Each of the headache outcomemeasures used for this analysis is as follows:

-   -   Headache relief efficacy at 1, 5, 15, and 30 minutes        post-treatment—headache relief efficacy is obtained when a        pre-treatment headache severity of mild, moderate, or severe        severity is improved to a post-treatment severity of none, mild,        or moderate respectively.    -   Headache free efficacy at 1, 5, 15, and 30 minutes        post-treatment—headache free efficacy is obtained when a        pre-treatment headache of mild, moderate, or severe severity is        improved to a post-treatment severity of none.    -   Headache recurrence within 24 hours post-treatment—recurrence        within 24 hours is defined as no or mild headache severity after        treatment that then worsened to moderate or severe headache        severity within 24 hours after treatment with no use of rescue        medication before the worsening.    -   Safety parameter—safety is defined as no adverse after-effects        of treatment.

For allergy, the rating of the intensity level depends on the extent towhich the allergy interferes with the ability to function. Mildallergies do not interfere with the ability to function, moderateallergies interfere with the ability to function but do not completelydisrupt the function, and severe allergies are incapacitating andcompletely disrupt the ability to function. The same outcome measures asfor headache were used for allergy.

B. Results and Discussion

Dosage

Initially, the effective nasal and oral, and maximum tolerable nasal andoral carbon dioxide flow rates were measured in seven subjects using alaboratory apparatus. The flow rate selected that is effective or themaximum tolerable rate varies with the individual. At low flow rates,the presence of the carbon dioxide produces a “tingling” sensationsimilar to that produced during drinking of carbonated beverages thatinadvertently enter the nasal passages e.g., “bubbles up the nose”. Thisis the effective rate and the tingling is a welcome sensation because itusually coincides with immediate relief of symptoms. Above a certainsubjectively determined flow rate the sensation becomes unpleasant,which may be described as a “stinging” or “burning” sensation. At astill higher flow rate (maximum tolerable rate), the stinging sensationbecomes intolerable and subjects remove the device from their nostril.Also, subjects are more sensitive to the first dose of a series for oneattack; subsequent doses give less or no sensation. The flow data showthat lower effective and maximum tolerable flow rates were selected bysubjects having no prior experience with the treatment (see Table IIIbelow). High flow rates were no prior tolerated orally than nasally. Thetypical effective rate nasally was 1 to 5 ml/sec and 5 to 10 ml/secorally.

TABLE III EFFECTIVE AND MAXIMUM TOLERABLE CARBON DIOXIDE FLOW RATESExpe- Max rience Effective Tolerable Max w/ Nasal Nasal EffectiveTolerable Age Gender Device Rate Rate Oral Rate Oral Rate (yrs) (m/f)(#) (ml/sec) (ml/sec) (ml/sec) (ml/sec) 43 f 0 <1 <1 >10*  >10* <1 47 f0 <1 2 5-10 >10* 9 m 0 1-2 3 5-10 >10* 44 m 0  2 4 2 >10* 45 m >10 4-510 5-10 >10* 72 m >1000 4-5 10 5-10 >10* 72 f >1000 4-5 10 5-10 >10**Maximum calibrated flow rate of flow meter was 10 ml/sec

For therapy, it is important to note that no number of doses, durationof dose, time between doses, or gas flow rates were specified for theuser. Subjects chose their own regimen for symptom relief. Analysis ofthe therapy data (see Table IV below) shows that the treatment is dosedependent. In general, milder attacks required fewer doses of shorterduration, thus a lower volume of gas, than severe attacks. Also,tension-type headaches required shorter average duration doses thanmigraine headaches (tension=24 sec, range=6-56 sec; migraine=57 sec,range=30-83 sec), and generally a lower volume of gas (tension=122 ml,range=28-288 ml; migraine=158 ml, range=82-233 ml). The average durationand total dose volume for headache and allergy treatment were similar(headache=32 sec and 124 ml; allergy=39 sec and 133 ml) as were thetotal treatment times (headache=7 mm; allergy=5 min).

TABLE IV EFFECTIVE CARBON DIOXIDE DOSE Single Est. Total Attack Type,No. of Dose Number Total Total Treatment Severity Attacks Duration ofDoses Dose Est. Rate Dose Time (N = No. of Subjects) (n) (sec) (#) (sec)(ml/sec) (ml) (min) Headache (N = 11) Migraine-Mild 6 23 1 30 3 82 1Migraine-Severe 4 35 2 83 3 233 28 Migraine-All 10 29 2 57 3 158 15Tension-Mild 3 3 2 6 3 28 2 Tension-Moderate 15 6 2 11 4 50 4Tension-Severe 7 15 4 56 5 288 11 Tension-All 25 8 3 24 4 122 6Headache-All 35 15 2 32 4 124 7 Allergy (N = 9) Allergy-Mild 1 15 2 40 5200 >0.7 Allergy-Moderate 2 3 2 16 2 31 >0.2 Allergy-Severe 6 17 2 46 4156 >3.9 Allergy-All 9 13 2 39 3 133 5

Headache

A total of 11 headache subjects with 35 headaches were assessed. Thesubjects were males (49%) and females (51%) ranging in age from 9 to 73years (mean=55) with mild (26%), moderate (43%), and severe (31%)headaches which included migraine (29%), tension-type (66%), and jawheadaches (5%). Headache duration before treatment averaged 2 hours(migraine=2.4 hours, tension=1.5 hours) and ranged from 0.3 to greaterthan 18 hours for migraines and 0.1 to 4 hours for tension-typeheadaches. The subjects with migraines had used the device from 0 to 8times and those with tension-type headache from 0 to 13 times with oneindividual who had not used it previously for headache but has used itfor allergies over 1000 times.

Using the efficacy outcome measures defined above, (which include mildheadaches, with relief defined as mild, moderate, or severe reduced tonone, mild, or moderate respectively) the present treatment had a 94%headache relief efficacy (migraine=90%, tension=96%) and an 80% headachefree efficacy (migraine=90%, tension=80%) for headaches at 30 minutespost-treatment (see Table V below). Considerable headache relief wasalso obtained at 15 minutes post-treatment (headache reliefefficacy=86%; headache free efficacy=74%). Subjects reported immediateonset of symptom relief within seconds while administering the firstdose. There were no instances of headache recurrence 24 hourspost-treatment with the gas therapy and no subjects reported any adverseafter effects of treatment.

TABLE V EFFICACY AND SAFETY - HEADACHE (MILD, MODERATE, SEVERE) SymptomRelief, Symptom Free, Minutes Minutes 24-hr. Attack Type Post-TreatmentPost-Treatment Recur After (N = No. No. of (%) (%) Rate Effects ofsubjects) Attacks (n) 1 5 15 30 1 5 15 30 (%) (%) Migraine (N = 2) 10 6060 60 90 60 60 60 90 0 0 Tension (N = 9) 25 20 64 96 96 20 64 80 80 0 0Headache-All 35 31 63 86 94 31 60 74 80 0 0

Using the more stringent IHS efficacy outcome measures (that excludemild headaches, with relief defined as moderate or severe reduced tomild or none) the treatment had the same average symptom headache freeefficacy of 80% (migraine=75%, tension=80%) for headache at 30 minutesas in the above analysis (see Table VI below). With these criteria, thetreatment had an 84% headache relief efficacy (migraine=100%,tension=77%) for headache at 30 minutes. Considerable headache reliefalso was obtained at 15 minutes post-treatment (headache reliefefficacy=72%; headache free efficacy=72%).

TABLE VI EFFICACY AND SAFETY - HEADACHE (MODERATE, SEVERE - IHSCRITERIA) Symptom, Relief, Symptom Free, Minutes Minutes 24-hr. AttackType Post-Treatment Post-Treatment Recur After (N = No. No. of (%) (%)Rate Effects of subjects) Attacks (n) 1 5 15 30 1 5 15 30 (%) (%)Migraine (N = 2) 4 25 25 25 100 25 25 25 75 0 0 Tension (N = 8) 22 14 5577 77 14 55 77 77 0 0 Headache-All 25 16 52 72 84 16 52 72 80 0 0

In summary, treatment of migraine and tension-type headache according tothe present invention shows 80-94% efficacy occurring in seconds tominutes (average treatment time=7 min) compared to 50-70% efficacy in2-4 hours with current drugs even though this was a dose-findinganalysis where the optimal dosing regimen was not defined. Thisfeasibility summary had many subjects who had never used the device, ornever used it for headaches, resulting in a number of instances wheretherapy was more efficacious after they learned the most effectivepersonal dosing regimen. For example, a subject suffering severe tensionheadaches tried on three occasions to eliminate the headaches with onlymoderate success using numerous doses of short duration (six doses of 8sec each=240 ml). Subsequently, she was able to completely eliminate asevere tension headache and a severe jaw/tooth ache with fewer doses oflonger duration (three doses of 15 sec each=225 ml and three doses of 45sec each=675 ml, respectively). As another example, a subject sufferinga moderate tension headache, who had never used the device forheadaches, tried to eliminate the headache with no success using anextremely small dose (one dose of 1 sec=2 ml). Finally, one patientsuffering from a migraine headache was unable to improve on a mildmigraine the first time he used the device (one dose for 30 sec=60 ml).However, he was able to completely eliminate all subsequent mild andsevere migraines with a dosage regimen he developed that increased thegas volume dose (two to three doses for 25 sec each=120 ml). He had ahistory of severe migraines bimonthly for over 25 years and had selectedsumatriptan (Imitrex®) by injection as a treatment prior to receivingthe device. Since he has tested the device of the present invention, hehas used no other headache medication and no longer has moderate orsevere migraines. When he first feels the onset of a migraine, he dosestwice for 20 to 25 seconds according to the present invention. Thiscompletely aborts the migraine and it does not recur. The frequency ofmigraine incidents has also decreased.

Allergy

There were 9 allergy subjects with 9 allergy attacks assessed. Thesubjects were males (67%) and (33%) females ranging in age from 9 to 72years (mean=39) with mild (11%), moderate (22%), and severe (67%)allergies which included symptoms in the nose, throat, and eyes).Allergy duration before treatment ranged from 0.2 to 1.5 hours. Thesubjects had used the device from 0 to over 1000 times.

The treatment achieved 100% allergy relief efficacy and an 89% allergyfree efficacy at both 15 and at 30 minutes (see Table VII below). Usingthe more stringent efficacy outcome measures (which exclude mildallergies and relief is defined as moderate or severe reduced to mild ornone) the treatment had essentially the same allergy relief efficacy andallergy free efficacy as in the above analysis. Subjects reportedimmediate onset of symptom relief within seconds while administering thefirst dose. There was a 50% recurrence of allergy symptoms; however, Nwas small (N=4) for this determination. The recurrences did not occuruntil 3 hours or longer post-treatment.

TABLE VII EFFICACY AND SAFETY - ALLERGY (MILD, MODERATE, SEVERE ANDMODERATE, SEVERE) Symptom, Relief, Symptom Free, Minutes Minutes 24-hr.Post-Treatment Post-Treatment Recur After Symptom No. of (%) (%) RateEffects Type Attacks (n) 1 5 15 30 1 5 15 30 (%) (%) Allergy (N = 9) 933 78 100 100 33 67 89 89 50 0 Allergy (N = 8)* 8 25 75 100 100 25 63 8888 50 0 *More stringent outcome measure definitions

In summary, treatment of allergic rhinitis according to the presentinvention shows 88-100% efficacy occurring in seconds to minutes(average treatment time=5 min) compared to minutes to hours with currentdrugs. No subjects reported any adverse after effects of treatment.

While the above is a complete description of the preferred embodimentsof the invention, various alternatives, modifications, and equivalentsmay be used. Therefore, the above description should not be taken aslimiting the scope of the invention that is defined by the appendedclaims.

1. A method for treating a headache in a patient in need of suchtreatment, said method comprising: releasing from a hand-held dispensera therapeutic, non-inhaled, dosage of a gas comprising at least 50%carbon dioxide by volume, wherein the hand-held dispenser is amulti-dose dispenser comprising a nosepiece and a flow regulator, theflow regulator comprising a flow-controlling orifice, and the hand-helddispenser configured to receive a carbon dioxide cartridge, wherein thegas is released from the nosepiece, and wherein the therapeutic dosageof the gas is accomplished at a flow rate from 1 cc/sec to 20 cc/sec fora duration of 2-30 seconds per nostril, the flow rate being repeatablycontrolled by the flow regulator; and instructing the patient tosubstantially refrain from inhaling while the gas is being released. 2.The method of claim 1, wherein the duration is from 2-10 seconds.
 3. Themethod of claim 1, wherein the dose is repeated from 1 to 10 times. 4.The method of claim 1, wherein the headache is a migraine headache. 5.The method of claim 1, wherein the hand held dispenser is a two-piecedispenser.
 6. The method of claim 1, wherein the hand held dispenser isa one-piece dispenser.
 7. The method of claim 1, wherein the headache isa tension-type headache.
 8. The method of claim 1, wherein the flow rateis selected by the patient.
 9. The method of claim 1, wherein thehand-held dispenser further comprises a pressure regulator.
 10. Themethod of claim 1, wherein the flow rate is from 4 cc/sec to 5 cc/sec.11. The method of claim 1, wherein the flow rate is from 1 cc/sec to 5cc/sec.
 12. The method of claim 1, wherein the flow rate is from 2cc/sec to 10 cc/sec.
 13. The method of claim 1, wherein the flow rate is10 cc/sec.
 14. The method of claim 1, wherein the gas comprises at least70% carbon dioxide.
 15. The method of claim 1, wherein the gas comprisesat least 95% carbon dioxide.
 16. The method of claim 1, wherein the gascomprises substantially pure carbon dioxide.